title: Functional variants of -1318T > G and -673C > T in c-Jun promoter region associated with increased colorectal cancer risk by elevating promoter activity.
abstract: C-Jun plays important roles in the development of multiple cancers, but no well-designed association studies have been conducted to assess the roles of its genetic polymorphisms in cancer risk. In a cohort of 1016 pairs of colorectal cancer (CRC) patients and matched cancer-free controls, we investigated two genetic polymorphisms in the promoter regions of the c-Jun (rs4646999, -673C > T and rs2760501, -1318T > G) via the Taqman assay and evaluated the association between two polymorphisms and risk of CRC. We found that both the -1318G and -673C variant genotypes were associated with an increased risk of CRC [-1318TG: odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.04-1.54; -1318GG: OR = 1.63, 95% CI = 1.03-2.60; -673CT: OR = 1.60, 95% CI = 1.23-2.07; -673CC: OR = 1.80, 95% CI = 1.36-2.37]. Haplotype association analysis showed that compared with the carriers of -1318T-673T haplotype, carriers of the -1318T-673C, -1318G-673T, and -1318G-673C haplotypes all had a significantly increased risk of CRC (P < 0.05 for all). The combined genotypes incorporating both polymorphisms obtained a more significantly additive risk of CRC (one variant genotype: OR = 1.81, 95% CI = 1.30-2.51; two variant genotype: OR = 2.42, 95% CI = 1.70-3.44). Moreover, we found that the change of the -1318T to G allele interact with the -673T to C allele elevated the transcription activity of the c-Jun, and we confirmed the same trends by analyzing c-Jun protein expression in the CRC tissues from patients carrying different number of variant genotypes. This study suggests that -673C > T and -1318T > G genetic variants in c-Jun promoter regions contribute to an increased risk of CRC, possibly by elevating the transcription activity and protein expression levels that appeared to upregulate activity of c-Jun thus tumorigenesis.
authors.affiliation: Gastrointestinal Institute, Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Erheng Road, Guangzhou 510655, People's Republic of China.
authors.forename: Dianke
authors.initials: D
authors.lastname: Chen
authors.forename: Shunxin
authors.initials: S
authors.lastname: Song
authors.forename: Jiachun
authors.initials: J
authors.lastname: Lu
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Luo
authors.forename: Zuli
authors.initials: Z
authors.lastname: Yang
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Huang
authors.forename: Xinhui
authors.initials: X
authors.lastname: Fu
authors.forename: Xinjuan
authors.initials: X
authors.lastname: Fan
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Wei
authors.forename: Jianping
authors.initials: J
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010957:Plasmids; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*
chemical_list: D016755:Proto-Oncogene Proteins c-jun